Composition improved in the solubility or oral absorbability

ABSTRACT

An object of the present invention is to provide a composition improved in the solubility or oral absorbability. The present invention provides a composition which comprises three components of a slightly water-soluble component, a surfactant and a hydrophilic polymer, and is obtainable by wet granulation in the presence of water.

TECHNICAL FIELD

The present invention relates to a composition improved in thesolubility or oral absorbability in a slightly water-soluble component.

BACKGROUND ART

In general, slightly water-soluble medicaments have poor oralabsorbability because of their low solubility and low dissolution ratein the digestive tracts. Various methods have been investigated toimprove the oral absorbability. Known examples of the methods include(a) a wet granulation method using a hydrophilic polymer, (b) a methodin which the medicament is fined by grinding, (c) a method in which asolid dispersion is formed with a polymer material, (d) a method inwhich a soluble clathrate is formed together with cyclodextrins, (e) amethod in which a surfactant is added, and the like.

The method (a) is known as a simple method in which the wettability towater of a medicament which is relatively water-insoluble can beimproved to raise the dissolution rate thereof [J. Pharm. Sci., 59, 49(1970) etc.] However, the effect is so limitative that the oralabsorbability of a medicament which is quite slightly water-solublecannot be sufficiently improved.

The method (b) is known as a method for raising the dissolution rate ofa slightly water-soluble medicament by increasing the surface areathereof [Dissolution Technology, the Industrial PharmaceuticalTechnology Section of the Academy of Pharmaceutical Science, p. 108(1974) etc.] However, the size to be fined by grinding is so limitativethat there are some problems that particles are aggregated or hardlywettable and the like when the finely ground medicaments are dispersedin water. Although a combination of the method (a) and the method (b) isfrequently used, this combination is still insufficient for improvingthe oral absorbability of a quite slightly water-soluble medicament.

When a solid dispersion is formed in the absence of water in accordancewith the method (c) (Japanese Published Unexamined Patent ApplicationNo. 110612/81 etc.), the solubility of a slightly water-solublemedicament is transiently increased upon the dispersion of the soliddispersion in water. However, there is a problem that the medicament iscrystallized after a definite period of time and thus the solubilitythereof is decreased. In addition, it is known that the stability of asolid dispersion obtained by the method (c) is sometimes decreased whenstored under highly humid conditions. Moreover, there is a furtherproblem that an organic solvent such as a halogenated solvent which isproblematic in safety is necessary in many cases in the step ofpreparing the solid dispersion of the medicament.

In the method (d), there are some medicaments which do not form aclathrate, because the formation of a clathrate depends on the structureof a medicament [Pharmaceutical Technology, 15, 24-38 (1991) etc.]

In the method (e), a large amount of a surfactant is necessary toimprove the solubility of a quite slightly water-soluble medicament.However, since many surfactants are in the form of liquid or wax, theysometimes disturb the preparation of a solid product. Even if thesolubility is improved, the oral absorbability is sometimes decreased bymicellation due to a surfactant depending on the properties of themedicament [Chemical & Pharmaceutical Bulletin, 18(8), 1563 (1970) etc.]

As a method for improving the bioavailability of a steroid medicamentwhich is less than 100 to 200 ng/ml, U.S. Pat. No. 4,684,636 discloses amethod wherein beads made of a saccharide or the like are coated with anaqueous suspension containing the steroid medicament, a binder and anoptional wetting agent and then are put into capsules. In this method,however, it is somewhat troublesome to produce the product and theeffect is still insufficient because an area under curve (AUC) of themedicament concentration in plasma is not more than twice as large asthat of a dry mixture of the medicament with an excipient free from awetting agent.

Under these circumstances, the composition which is easily used and hashigh effects, in which a slightly water-soluble component has improvedsolubility or oral absorbability, has been required.

DISCLOSURE OF THE INVENTION

The present invention relates to the following (1) to (21).

(1) A composition which comprises three components of a slightlywater-soluble component, a surfactant and a hydrophilic polymer, and isobtainable by wet granulation in the presence of water.

(2) The composition according to (1), wherein the slightly water-solublecomponent is a slightly water-soluble medicament.

(3) The composition according to (1), wherein the slightly water-solublecomponent is a slightly water-soluble food component.

(4) The composition according to any one of (1) to (3), which comprisesan excipient.

(5) The composition according to any one of (1) to (4), wherein thesurfactant is one or more surfactants selected from the group consistingof sodium lauryl sulfate, polysorbate 80, polysorbate 60,polyoxyethylene hydrogenated castor oil, polyoxyethylenepolyoxypropylene glycol and sucrose fatty acid esters.

(6) The composition according to any one of (1) to (5), wherein thehydrophilic polymer is one or more hydrophilic polymers selected fromthe group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, carboxymethyl cellulose, carboxymethylethyl cellulose, hydroxypropyl starch, hydroxyethyl cellulose,hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, carboxyvinyl polymer, polyvinylpyrrolidone,polyvinyl alcohol, methacrylic acid copolymers, macrogol, starch,gelatin, dextrin, pullulan, agar and acacia.

(7) The composition according to any one of (1) to (5), wherein thehydrophilic polymer is one or more hydrophilic polymers selected fromthe group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone.

(8) The composition according to any one of (4) to (7), wherein theexcipient is one or more excipients selected from the group consistingof lactose, sucrose, starch, crystalline cellulose, D-mannitol,D-sorbitol, a starch derivative, a cellulose derivative, a carbonate, aphosphate and a sulfate.

(9) The composition according to any one of (4) to (7), wherein theexcipient is one or more excipients selected from the group consistingof starch, crystalline cellulose and D-mannitol.

(10) The composition according to any one of (1) and (4) to (9), whereinthe slightly water-soluble component is a steroid medicament.

(11) The composition according to any one of (1) and (4) to (9), whereinthe slightly water-soluble component is a compound represented byformula (1) [hereinafter referred to as Compound (I)]:

wherein R represents NR¹R², in which R¹ and R² are the same or differentand each represents hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted aryl or a substituted or unsubstitutedaromatic heterocyclic group, or R¹ and R² form a substituted orunsubstituted heterocyclic group together with the adjacent nitrogenatom.

(12) The composition according to (11), wherein R¹ and R² are the sameor different and each represents hydrogen or substituted orunsubstituted alkyl.

(13) The composition according to (11), wherein R¹ and R² are the sameor different and each represents hydrogen or alkyl having 1 to 5 carbonatoms.

(14) The composition according to (11), wherein R is NHCH₂CH₂CH₃,N(CH(CH₃)₂)₂ or NHC(CH₃)₃.

(15) The composition according to any one of (1) to (4) and (8) to (14),wherein the surfactant is sodium lauryl sulfate, and the hydrophilicpolymer is hydroxypropyl cellulose.

(16) The composition according to any one of (1) to (4) and (8) to (14),wherein the surfactant is sodium lauryl sulfate, and the hydrophilicpolymer is hydroxypropyl methyl cellulose.

(17) The composition according to any one of (1) to (4) and (8) to (14),wherein the surfactant is sodium lauryl sulfate, and the hydrophilicpolymer is polyvinylpyrrolidone.

(18) The composition according to any one of (1) to (17), wherein thewet granulation is carried out by a wet granulation method by stirring.

(19) The composition according to any one of (1) and (4) to (9), whereinthe slightly water-soluble component is ubidecarenone or a fat-solublevitamin.

(20) A method for improving the solubility of a slightly water-solublecomponent, which comprises subjecting the slightly water-solublecomponent to wet granulation together with a surfactant and ahydrophilic polymer in the presence of water.

(21) A method for improving the oral absorbability of a slightlywater-soluble component, which comprises subjecting the slightlywater-soluble component to wet granulation together with a surfactantand a hydrophilic polymer in the presence of water.

The composition of the present invention is not particularly limited, solong as it contains three components of a slightly water-solublecomponent, a surfactant and a hydrophilic polymer and is obtainable bywet granulation in the presence of water.

The slightly water-soluble component includes a slightly water-solublemedicament, a slightly water-soluble food component, and the like.

The slightly water-soluble medicament is not particularly limited, andincludes any medicaments considered to be “slightly water-soluble” or“quite slightly soluble in water” according to The Pharmacopoeia ofJapan. The slightly water-soluble medicament includes nifedipine,γ-oryzanol, indomethacin, rifampicillin, griseofulvin, mefenamic acid,corticosteroid, fenitoine, ubidecarenone (coenzyme Q₁₀), fat-solublevitamins, steroid medicaments, nonsteroid medicaments, and the like.

The ubidecarenone in the present specification includes precursors,prodrugs and the like which can be converted into ubidecarenone in vivo.

The slightly water-soluble medicament is preferably a hydrophobicsteroid medicament or a hydrophobic nonsteroid medicament.

The hydrophobic nonsteroid medicament includes xanthine medicaments,dibenzoxepine medicaments and the like, and is preferably Compound (II)which is a xanthine medicament:

wherein R³ and R⁴ are the same or different and each representssubstituted or unsubstituted alkyl; and R⁵ represents substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted bicycloalkyl, or substituted orunsubstituted tricycloalkyl, Compound (III) which is a dibenzoxepinemedicament:

wherein R⁶ and R⁷ are the same or different and each representssubstituted or unsubstituted alkyl; and R⁸ represents halogen, or thelike. Examples of Compound (II) include Compound (IIa) represented bythe following formula (IIa):

Examples of Compound (III) include Compound (IIIa) represented by thefollowing formula (IIIa):

The hydrophobic nonsteroid medicament includes Compounds (I), and ispreferably a compound which is Compound (I) wherein R representsNHCH₂CH₂CH₃, N(CH(CH₃)₂)₂ or NHC(CH₃)₃ [referred to as Compound (Ia),(Ib) or (Ic), respectively] or the like.

In the definition of each group in Compounds (I) to (III), the alkylincludes linear or branched alkyl having, for example, 1 to 15 carbonatoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl,dodecyl, tridecyl, tetradecyl and pentadecyl.

The aryl includes aryl having, for example, 6 to 14 carbon atoms, suchas phenyl, naphthyl and anthryl.

The aromatic heterocyclic group includes a 3- to 8-membered monocyclicaromatic heterocyclic group containing at least one atom selected from anitrogen atom, an oxygen atom and a sulfur atom, a fused bicyclic ortricyclic aromatic heterocyclic group in which 3- to 8-membered ringsare fused, containing at least one atom selected from a nitrogen atom,an oxygen atom and a sulfur atom, and the like. Examples include furyl,thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, furazanyl, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, quinolyl, quinoxalinyl, isoquinolyl,quinazolinyl, phthalazinyl, purinyl, indolyl, indazolyl, benzimidazolyl,isoindolyl, 2-pyridonyl, 4-pyridonyl, uracilyl, benzofuryl, benzothienyland the like.

The heterocyclic group formed together with the adjacent nitrogen atomincludes a 5- or 6-membered monocyclic heterocyclic group containing atleast one nitrogen atom (the monocyclic heterocyclic group may containother nitrogen atom(s), oxygen atom(s) or sulfur atom(s)), a fusedbicyclic or tricyclic heterocyclic group in which 3- to 8-membered ringsare fused together, containing at least one nitrogen atom (the fusedheterocyclic group may contain other nitrogen atom(s), oxygen atom(s) orsulfur atom(s)), and the like. Examples include pyrrolidinyl,piperidino, piperazinyl, morpholino, thiomorpholino, homopiperidino,homopiperazinyl, tetrahydropyridinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, pyrrolyl, imidazolyl, pyrazolyl and the like.

The cycloalkyl includes cycloalkyl having, for example, 3 to 9 carbonatoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl and cyclononyl.

The bicycloalkyl includes bicycloalkyl having, for example, 7 to 12carbon atoms such as bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl andbicyclo[3.3.1]nonyl.

The tricycloalkyl includes tricycloalkyl having, for example, 9 or 10carbon atoms such as adamantyl and n-adamantyl.

The halogen includes a fluorine atom, a chlorine atom, a bromine atomand an iodine atom.

The substituents in the substituted alkyl, the substituted cycloalkyl,the substituted bicycloalkyl and the substituted tricycloalkyl are thesame or different and, for example, 1 to 3 substituents such as hydroxyor halogen. The substituents in the substituted aryl, the substitutedaromatic heterocyclic group and the substituted heterocyclic groupformed together with the adjacent nitrogen atom are the same ordifferent and, for example, 1 to 3 substituents such as alkyl, hydroxyor halogen. In the above definitions, the alkyl and the halogen have thesame meanings as defined above, respectively.

The slightly water-soluble medicament can be used either as a free form(i.e., a form in which a salt is not formed) or as a pharmaceuticallyacceptable salt. As for the pharmaceutically acceptable salt, examplesinclude pharmaceutically acceptable acid addition salts, metal salts,ammonium salts, organic amine addition salts, amino acid addition saltsand the like. The acid addition salts include inorganic acid salts suchas hydrochlorides, hydrobromides, sulfates, phosphates and nitrates; andorganic acid salts such as acetates, fumarates, maleates, tartrates,citrates, lactates, oxalates, methanesulfonates, benzenesulfonates andp-toluenesulfonates. The metal salts include alkali metal salts such aslithium salts, sodium salts and potassium salts; alkaline earth metalsalts such as magnesium salts and calcium salts; aluminum salts; zincsalts; and the like. The ammonium salts include salts of ammonium,tetramethylammonium and the like. The organic amine addition saltsinclude addition salts of morpholine, piperidine or the like. The aminoacid addition salts include addition salts of glycine, phenylalanine,aspartic acid, glutamic acid, lysine or the like.

The slightly water-soluble food component includes ubidecarenone,fat-soluble vitamins and the like.

The fat-soluble vitamins include vitamin A, vitamin D, vitamin E,vitamin F, vitamin K, vitamin U and the like, and a preferablefat-soluble vitamin is vitamin K. Further, “fat-soluble vitamins” in thepresent specification also include precursors, prodrugs and the like ofvitamin A, vitamin D, vitamin E, vitamin F, vitamin K, vitamin U and thelike which can be converted into these vitamins in vivo.

The slightly water-soluble food component can be used either as a freeform (i.e., a form in which a salt is not formed) or as a salt. The saltof the slightly water-soluble food component includes salts exemplifiedas the above pharmaceutically acceptable salts of the slightlywater-soluble medicament.

The surfactant is not particularly limited, so long as it can be orallyadministered. Examples include sodium lauryl sulfate, polysorbate 80,polysorbate 60, polysorbate 40, polysorbate 20, poloxyl 10 oleyl ether,poloxyl 20 cetostearyl ether, poloxyl 20 cetyl ether, polyoxyethylenehydrogenated castor oil, poloxyl 40 stearate, poloxyl 50 stearate,polyoxyethylene polyoxypropylene glycol, sucrose fatty acid esters andthe like, which may be used in combination of two or more thereof.Preferable examples include sodium lauryl sulfate, polysorbate 80,polysorbate 60, polyoxyethylene hydrogeneated castor oil,polyoxyethylene polyoxypropylene glycol, sucrose fatty acid esters andthe like (two or more surfactants selected from sodium lauryl sulfate,polysorbate 80, polysorbate 60, polyoxyethylene hydrogenated castor oil,polyoxyethylene polyoxypropylene glycol and sucrose fatty acid estersmay be used in combination). More preferable examples include sodiumlauryl sulfate, polysorbate 80, sucrose fatty acid esters and the like(two or more surfactants selected from sodium lauryl sulfate,polysorbate 80 and sucrose fatty acid esters may be used incombination).

The hydrophilic polymer is not particularly limited, so long as it issoluble in water or swellable in water and can be used as a binder.Non-limited examples include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, carboxymethyl cellulose,carboxymethyl ethyl cellulose, hydroxypropyl starch, hydroxyethylcellulose, hydroxypropyl methyl cellulose acetate succinate,hydroxypropyl methyl cellulose phthalate, carboxyvinyl polymer,polyvinylpyrrolidone, polyvinyl alcohol, methacrylic acid copolymers,macrogol, starch, gelatin, dextrin, pullulan, agar, acacia and the like,which may be used in combination of two or more thereof. Preferableexamples include hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone and the like (two or more hydrophilicpolymers selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone may be used in combination).

The content of the slightly water-soluble component in the compositionof the present invention is not particularly limited, and is preferably0.0001 to 0.5 g, more preferably 0.01 to 0.3 g, per gram of thecomposition.

The weight ratio of the slightly water-soluble component to thesurfactant and hydrophilic polymer is not particularly limited, and theratio of slightly water-soluble component:surfactant:hydrophilic polymeris preferably 1:0.1 to 50:0.01 to 20, more preferably 1:0.5 to 20:0.1 to10.

The slightly water-soluble component, surfactant and hydrophilic polymerto be used in the present invention may be obtained as commerciallyavailable products or produced by known methods. Particularly, Compounds(I), (II) and (III), including novel compounds, can be produced,respectively by the methods described in WO 00/43408, Japanese PublishedUnexamined Patent Application No. 173889/91, Japanese PublishedUnexamined Patent Application No. 132477/93 and the like or by modifiedmethods thereof. The desired compound in the production process can beisolated and purified according to the conventional purification methodused in the field of synthetic organic chemistry such as filtration,extraction, washing, drying, concentration, recrystallization or variouschromatographies. In the production of a salt of Compound (I), (II) or(III), when Compound (I), (II) or (III) is obtained in the form of asalt, it may be purified as such, and when Compound (I), (II) or (III)is in the form of a free salt, it may be dissolved or suspended in anappropriate solvent and then an acid or base is added thereto to form asalt.

The wet granulation in the present invention represents production ofgranulated powder having an almost uniform shape and size from a wetpowdery or block material, preferably production of granulated powderhaving an almost uniform shape and size from a wet powdery material. Theaddition of the hydrophilic polymer during the wet granulation may becarried out by a method in which the hydrophilic polymer is added in asolid state or a method in which the hydrophilic polymer is dissolved inan aqueous solvent and then added as a solution.

The aqueous solvent used in the wet granulation in the present inventionincludes water and a water/organic solvent mixture. Examples includewater, water/ethanol, water/isopropyl alcohol, water/acetone and thelike, and water is preferred. The weight of the aqueous solvent used inthe wet granulation in the present invention is not particularlylimited, and it is preferable to use the slightly water-solublecomponent and the aqueous solvent at a weight ratio of 1:0.01 to 0.5,the weight ratio having more preferably 1:0.05 to 0.2. As an apparatusused for the granulation procedure in the present invention, anygranulation apparatuses usually used, such as a stirring type, a flowtype, a roll-flow type or an extrusion type, can be used withoutlimitation. A mortar or the like may also be used.

The composition of the present invention may contain an excipient. Forexample, an excipient may be added during the granulation procedure asdescribed above.

The excipient is not particularly limited, and includes lactose,sucrose, starch, crystalline cellulose, D-mannitol, D-sorbitol, starchderivatives (corn starch etc.), cellulose derivatives, carbonates,phosphates, sulfates and the like, which may be used alone or incombination of two or more thereof. Preferable examples includeD-mannitol, lactose, D-mannitol/starch, lactose/starch,D-mannitol/crystalline cellulose, lactose/crystalline cellulose,D-mannitol/starch/crystalline cellulose, lactose/starch/crystallinecellulose and the like. More preferable examples include starch,crystalline cellulose, D-mannitol and the like (two or more excipientsselected from starch, crystalline cellulose and D-mannitol may be usedin combination). D-Manntiol/starch is still more preferable.

In the present invention, the excipient can be used in an amount of 0-to 1000-folds by weight as much as the slightly water-soluble component(Use of 0-fold by weight of the excipient as much as the slightlywater-soluble component means that no excipient is used).

In addition, the composition of the present invention may contain adisintegrator, a lubricant or the like, if necessary. The disintegratorincludes crospovidone, croscarmellose sodium, sodium carboxymethylstarch, low substituted hydroxypropyl cellulose and the like, althoughit is not limited thereto. The lubricant includes magnesium stearate,calcium stearate, talc, glyceryl monostearate, light anhydrous silicicacid and the like.

Furthermore, the composition of the present invention may contain acoloring agent, a flavor or the like, if necessary. The coloring agentincludes titanium oxide, talc, ferric oxide, yellow ferric oxide, blackiron oxide, copper chlorophyll, copper chlorophylline sodium, carbonblack, carbon for medical use, various edible colorants, glycyrrhizaextract, green tea powder, riboflavin, riboflavin butyrate, riboflavinsodium phosphate, octyldodecyl myristate and the like. The flavorincludes fennel powder, fennel oil, ethyl vanillin, orange extract,orange oil, orange essence, capsicum flavor, glycyrrhiza extract,cinnamon bark powder, cinnamon oil, cherry flavor, clove oil, turpentineoil, bitter orange peel powder, peppermint oil, vanilla flavor,vanillin, bitter essence, bergamot flavor, menthol, eucalyptus oil,borneol, rosin and the like.

The composition of the present invention can be formulated into granulesor fine granules. Also, it can be encapsulated to give capsules ortableted to give tablets.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows changes in the concentration of Compound (Ia) in the plasmawhen a solid composition containing 0.01 g of Compound (Ia) wasadministered to a beagle.

FIG. 2 shows changes in the concentration of Compound (Ib) in the plasmawhen a solid composition or injection each containing 0.01 g of Compound(Ib) was administered to a beagle.

Symbols used in FIGS. 1 and 2 are described below.

-◯-: Changes in the concentration of Compound (Ia) in plasma when thecomposition of Example 11 was orally administered.

-□-: Changes in the concentration of Compound (Ia) in plasma when thecomposition of Comparative Example 4 was orally administered.

-Δ-: Changes in the concentration of Compound (Ia) in plasma when thecomposition of Comparative Example 5 was orally administered.

-●-: Changes in the concentration of Compound (Ib) in plasma when thecomposition of Example 28 was orally administered.

--◯--: Changes in the concentration of Compound (Ib) in plasma when thecomposition of Example 29 was orally administered.

-▴-: Changes in the concentration of Compound (Ib) in plasma when thecomposition of Example 30 was orally administered.

--□--: Changes in the concentration of Compound (Ib) in plasma when thecomposition of Example 31 was orally administered.

-▪-: Changes in the concentration of Compound (Ib) in plasma when theinjection of Comparative Example 11 was intravenously administered.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is described below in detail based on Examples.However, the present invention is not limited thereto.

EXAMPLE 1

In a mortar, 0.05 g of Compound (la), 0.1 g of sodium lauryl sulfate,0.6 g of D-mannitol, 0.25 g of corn starch and 0.02 g of hydroxypropylcellulose (HPC-SSL) were granulated by kneading with a pestle whilewater was dropped thereto. After drying at 60° C. for 30 minutes, thegranulated powder was sifted out with a sieve of 420 μm mesh to give apowdery solid composition.

EXAMPLE 2

In a mortar, 0.1 g of Compound (la), 0.2 g of sodium lauryl sulfate,1.16 g of D-mannitol, 0.5 g of corn starch and 0.04 g ofhydroxypropylmethyl cellulose were granulated by kneading with a pestlewhile water was dropped thereto. After drying at 60° C. for 1 hour, thegranulated powder was sifted out with a sieve of 500 μm mesh to give apowdery solid composition.

EXAMPLE 3

In a mortar, 0.1 g of Compound (Ia), 0.2 g of sodium lauryl sulfate,1.16 g of D-mannitol, 0.5 g of corn starch and 0.04 g ofpolyvinylpyrrolidone were granulated by kneading with a pestle whilewater was dropped thereto. After drying at 60° C. for 1 hour, thegranulated powder was sifted out with a sieve of 500 μm mesh to give apowdery solid composition.

EXAMPLE 4

In a high-shear mixer type tablet mill, 0.5 g of Compound (Ia), 1.0 g ofsodium lauryl sulfate, 5.8 g of D-mannitol, 2.5 g of corn starch and 0.2g of hydroxyproypl cellulose (HPC-SSL) were fed and granulated for about5 minutes while water was dropped thereto. After drying at 60° C. for 1hour, the granulated powder was sifted out with a sieve of 500 μm meshto give a granular solid composition.

EXAMPLE 5

In a high-shear mixer type tablet mill, 0.5 g of Compound (Ia), 1.0 g ofsodium lauryl sulfate, 5.8 g of D-mannitol and 2.5 g of corn starch werefed and granulated for about 5 minutes while 1.2 g of an aqueoussolution of 16.7% by weight hydroxypropyl cellulose (HPC-SSL) and asmall amount of water were dropped thereto. After drying at 60° C. for 1hour, the granulated powder was sifted out with a sieve of 500 μm meshto give a granular solid composition.

EXAMPLE 6

A tablet was obtained by mixing 0.2 g of the solid composition obtainedin Example 4 with 0.01 g of crospovidone and compressing them in an oilhydraulic press under 3 MPa pressure.

EXAMPLE 7

In a high-shear mixer type tablet mill, 0.5 g of Compound (Ia), 0.5 g ofsodium lauryl sulfate, 6.3 g of D-mannitol, 2.5 g of corn starch and 0.2g of hydroxyproypl cellulose (HPC-SSL) were fed and granulated for about5 minutes while water was dropped thereto. After drying at 60° C. for 1hour, the granulated powder was sifted out with a sieve of 500 μm meshto give a granular solid composition (In the composition of Example 7,the added amount of sodium lauryl sulfate is a half of that of thesodium lauryl sulfate in the composition of Example 4).

EXAMPLE 8

In a high-shear mixer type tablet mill, 0.5 g of Compound (Ia), 1.0 g ofsodium lauryl sulfate, 5.7 g of D-mannitol, 2.5 g of corn starch and 0.3g of hydroxyproypl cellulose (HPC-SSL) were fed and granulated for about5 minutes while water was dropped thereto. After drying at 60° C. for 1hour, the granulated powder was sifted out with a sieve of 500 μm meshto give a granular solid composition (In the composition of Example 8,the added amount of hydroxyproypl cellulose (HPC-SSL) is 1.5-foldshigher than that of the hydroxyproypl cellulose (HPC-SSL) in thecomposition of Example 4).

EXAMPLE 9

In a high-shear mixer type tablet mill, 0.5 g of Compound (Ia), 1.0 g ofsodium lauryl sulfate, 5.9 g of D-mannitol, 2.5 g of corn starch and 0.1g of hydroxyproypl cellulose (HPC-SSL) were fed and granulated for about5 minutes while water was dropped thereto. After drying at 60° C. for 1hour, the granulated powder was sifted out with a sieve of 500 μm meshto give a granular solid composition (In the composition of Example 9,the added amount of hydroxyproypl cellulose (HPC-SSL) is a half of thatof the hydroxyproypl cellulose (HPC-SSL) in the composition of Example4).

EXAMPLE 10

In a high-shear mixer type tablet mill, 0.5 g of Compound (Ia), 1.0 g ofsodium lauryl sulfate, 5.8 g of D-mannitol, 2.5 g of corn starch and 0.2g of hydroxyproypl cellulose (HPC-SSL) were fed and granulated for about15 minutes while water was dropped thereto. After drying at 60° C. for 1hour, the granulated powder was sifted out with a sieve of 500 μm meshto give a granular solid composition (The granulation time in Example 10is different from that in Example 4).

EXAMPLE 11

A capsule preparation was obtained by filing 0.2 g of the solidcomposition obtained in Example 4 (corresponding to 0.01 g of Compound(Ia)) in a gelatin capsule (manufactured by Shionogi Qualicaps).

EXAMPLE 12

A powdery solid composition was obtained by carrying out wetgranulation, drying and sieving in the same manner as in Example 1 byusing Compound (Ib) instead of Compound (Ia).

EXAMPLE 13

A powdery solid composition was obtained by carrying out wetgranulation, drying and sieving in the same manner as in Example 1 byusing Compound (Ic) instead of Compound (Ia).

EXAMPLE 14

In a mortar, 0.6 g of Compound (IIa), 1.2 g of sodium lauryl sulfate and0.24 g of hydroxypropyl cellulose (HPC-SSL) were granulated by kneadingwith a pestle while water was dropped thereto. After drying at 60° C.for 60 minutes, a powdery solid composition was obtained.

EXAMPLE 15

In a mortar, 0.6 g of Compound (IIIa), 1.2 g of sodium lauryl sulfateand 0.24 g of hydroxypropyl cellulose (HPC-SSL) were granulated bykneading with a pestle while water was dropped thereto. After drying at60° C. for 60 minutes, a powdery solid composition was obtained.

EXAMPLE 16

In a mortar, 0.1 g of ubidecarenone, 0.2 g of sodium lauryl sulfate,1.66 g of D-mannitol and 0.04 g of hydroxyproypl cellulose (HPC-SSL)were granulated by kneading with a pestle for about 2 minutes whilewater was dropped thereto. After drying at 40° C. for 1 hour, thegranulated powder was sifted out with a sieve of 500 μm mesh to give apowdery solid composition.

EXAMPLE 17

In a mortar, 0.1 g of ubidecarenone, 0.2 g of sodium lauryl sulfate,1.66 g of D-mannitol and 0.04 g of hydroxyproypl cellulose (HPC-SSL)were granulated by kneading with a pestle for about 10 minutes whilewater was dropped thereto. After drying at 40° C. for 1 hour, thegranulated powder was sifted out with a sieve of 500 μm mesh to give apowdery solid composition.

EXAMPLE 18

In a mortar, 1.2 g of ubidecarenone was mixed with 1.8 g of sodiumlauryl sulfate for 3 minutes, and 2.5 g of the mixture, 7.2 g ofD-mannitol and 0.3 g of hydroxyproypl cellulose (HPC-SSL) were fed in ahigh-shear mixer type tablet mill and granulated for about 25 minuteswhile water was dropped thereto. After drying at 40° C. for 2 hours, thegranulated powder was sifted out with a sieve of 500 μm mesh to give agranular solid composition.

EXAMPLE 19

In a high-shear mixer type tablet mill, 0.5 g of Compound (Ib) having anaverage particle diameter size of 3 μm, 1.0 g of sodium lauryl sulfate,5.8 g of D-mannitol, 2.5 g of corn starch and 0.2 g of hydroxyproyplcellulose (HPC-SSL) were fed and granulated for about 4 minutes whilewater was dropped thereto. After drying at 60° C. for 2 hours, thegranulated powder was sifted out with a sieve of 500 μm mesh to give agranular solid composition.

EXAMPLE 20

In a high-shear mixer type tablet mill, 0.5 g of Compound (Ib) having anaverage particle diameter size of 29 μm, 1.0 g of sodium lauryl sulfate,5.8 g of D-mannitol, 2.5 g of corn starch and 0.2 g of hydroxyproyplcellulose (HPC-SSL) were fed and granulated for about 4 minutes whilewater was dropped thereto. After drying at 60° C. for 2 hours, thegranulated powder was sifted out with a sieve of 500 μm mesh to give agranular solid composition.

EXAMPLE 21

In a high-shear mixer type tablet mill, 0.5 g of Compound (Ib) having anaverage particle diameter size of 29 μm, 1.0 g of sodium lauryl sulfateand 0.2 g of hydroxyproypl cellulose (HPC-SSL) were fed and granulatedfor about 5 minutes while water was dropped thereto. Further, 5.8 g ofD-mannitol and 2.5 g of corn starch was added thereto and the mixturewas granulated for about 30 minutes while water was dropped thereto.After drying at 60° C. for 2 hours, the granulated powder was sifted outwith a sieve of 500 μm mesh to give a granular solid composition.

EXAMPLE 22

Using a jet mill, 1.0 g of Compound (Ib) having an average particlediameter size of 94 μm and 2.0 g of sodium lauryl sulfate were ground togive a ground product. In a high-shear mixer type tablet mill, 1.5 g ofthe ground product, 5.8 g of D-mannitol, 2.5 g of corn starch and 0.2 gof hydroxyproypl cellulose (HPC-SSL) were fed and granulated for about 4minutes while water was dropped thereto. After drying at 60° C. for 2hours, the granulated powder was sifted out with a sieve of 500 μm meshto give a granular solid composition.

EXAMPLE 23

In a high-shear mixer type tablet mill, 0.5 g of Compound (Ib) having anaverage particle diameter size of 5 μm, 1.0 g of sodium lauryl sulfate,5.8 g of D-mannitol, 2.5 g of corn starch and 0.2 g of hydroxyproyplcellulose (HPC-SSL) were fed and granulated for about 4 minutes whilewater was dropped thereto. After drying at 60° C. for 2 hours, thegranulated powder was sifted out with a sieve of 500 μm mesh to give agranular solid composition.

EXAMPLE 24

In a high-shear mixer type tablet mill, 0.5 g of Compound (Ib) having anaverage particle diameter size of 5 μm, 1.0 g of jet-ground sodiumlauryl sulfate, 5.8 g of D-mannitol, 2.5 g of corn starch and 0.2 g ofhydroxyproypl cellulose (HPC-SSL) were fed and granulated for about 7minutes while water was dropped thereto. After drying at 60° C. for 2hours, the granulated powder was sifted out with a sieve of 500 μm meshto give a granular solid composition.

EXAMPLE 25

In a high-shear mixer type tablet mill, 0.5 g of Compound (Ib) having anaverage particle diameter size of 5 μm, 1.0 g of sodium lauryl sulfate,8.3 g of D-mannitol and 0.2 g of hydroxyproypl cellulose (HPC-SSL) werefed and granulated for about 3 minutes while water was dropped thereto.After drying at 60° C. for 2 hours, the granulated powder was sifted outwith a sieve of 500 μm mesh to give a granular solid composition.

EXAMPLE 26

In a high-shear mixer type tablet mill, 0.5 g of Compound (Ib) having anaverage particle diameter size of 5 Mm, 1.0 g of sodium lauryl sulfate,5.8 g of D-mannitol, 2.5 g of corn starch and 0.2 g of hydroxyproyplcellulose (HPC-SSL) were fed and granulated for about 4 minutes whilewater was dropped thereto. After drying at 60° C. for 2 hours, thegranulated powder was sifted out with a sieve of 500 μm mesh to give agranular solid composition.

EXAMPLE 27

In a vinyl bag, 0.5 g of Compound (Ib) having an average particlediameter size of 5 μm, 1.0 g of sodium lauryl sulfate and 0.2 g ofhydroxyproypl cellulose (HPC-SSL) were mixed together for I minute.Separately, in a vinyl bag, 5.8 g of D-mannitol and 2.5 g of corn starchwere mixed together for I minute. Both of the mixtures were fed in ahigh-shear mixer type tablet mill and granulated for about 4 minuteswhile water was dropped thereto. After drying at 60° C. for 2 hours, thegranulated powder was sifted out with a sieve of 500 μm mesh to give agranular solid composition.

EXAMPLE 28

A capsule preparation was obtained by filling 0.2 g of the solidcomposition obtained in Example 19 (corresponding to 0.01 g of Compound(Ib)) in a gelatin capsule (manufactured by Shionogi Qualicaps).

EXAMPLE 29

A capsule preparation was obtained by filling 0.2 g of the solidcomposition obtained in Example 20 (corresponding to 0.01 g of Compound(Ib)) in a gelatin capsule (manufactured by Shionogi Qualicaps).

EXAMPLE 30

A capsule preparation was obtained by filing 0.2 g of the solidcomposition obtained in Example 21 (corresponding to 0.01 g of Compound(Ib)) in a gelatin capsule (manufactured by Shionogi Qualicaps).

EXAMPLE 31

A capsule preparation was obtained by filling 0.2 g of the solidcomposition obtained in Example 22 (corresponding to 0.01 g of Compound(Ib)) in a gelatin capsule (manufactured by Shionogi Qualicaps).

COMPARATIVE EXAMPLE 1

In a mortar, 0.05 g of Compound (Ia), 0.1 g of sodium lauryl sulfate,0.6 g of D-mannitol, 0.25 g of corn starch and 0.02 g of hydroxypropylcellulose (HPC-SSL) were mixed with a pestle to give a powdery solidcomposition (As the difference, wet granulation is carried out inExample 1, whereas wet granulation is not carried out in ComparativeExample 1).

COMPARATIVE EXAMPLE 2

In a mortar, 0.05 g of Compound (Ia), 0.1 g of sodium lauryl sulfate,0.6 g of D-mannitol and 0.25 g of corn starch were granulated bykneading with a pestle while water was dropped thereto. After drying at60° C. for 30 minutes, the granulated powder was sifted out with a sieveof 420 μm mesh to give a powdery solid composition (As the difference,the solid composition of Example 1 contains a hydrophilic polymer,whereas the solid composition of Comparative Example 2 contains nohydrophilic polymer).

COMPARATIVE EXAMPLE 3

In a mortar, 0.05 g of Compound (Ia), 0.6 g of D-mannitol, 0.25 g ofcorn starch and 0.02 g of hydroxypropyl cellulose (HPC-SSL) weregranulated by kneading with a pestle while water was dropped thereto.After drying at 60° C. for 30 minutes, the granulated powder was siftedout with a sieve of 420 μm mesh to give a powdery solid composition (Asthe difference, the solid composition of Example 1 contains asurfactant, whereas the solid composition of Comparative Example 3contains no surfactant).

COMPARATIVE EXAMPLE 4

In a mortar, 0.1 g of Compound (Ia) and 0.9 g of D-mannitol were mixedin a mortar. Then 0.1 g of this mixture (corresponding to 0.01 g ofCompound (Ia)) was filled in a gelatin capsule (manufactured by ShionogiQualicaps) to give a capsule preparation.

COMPARATIVE EXAMPLE 5

In a mortar, 0.1 g of Compound (Ia), 0.2 g of sodium lauryl sulfate and0.9 g of D-mannitol were mixed. A capsule preparation was obtained byfilling 0.12 g of the mixture (corresponding to 0.01 g of Compound (Ia))in a gelatin capsule (manufactured by Shionogi Qualicaps).

COMPARATIVE EXAMPLE 6

A powdery solid composition was obtained by mixing the same componentsin a mortar at the same ratio as in Example 12.

COMPARATIVE EXAMPLE 7

A powdery solid composition was obtained by mixing the same componentsin a mortar at the same ratio as in Example 13.

COMPARATIVE EXAMPLE 8

In a mortar, 0.6 g of Compound (IIIa), 1.2 g of sodium lauryl sulfateand 0.24 g of hydroxypropyl cellulose (HPC-SSL) were mixed to give apowdery solid composition.

COMPARATIVE EXAMPLE 9

In a mortar, 0.6 g of Compound (IIIa), 1.2 g of sodium lauryl sulfateand 0.24 g of hydroxypropyl cellulose (HPC-SSL) were mixed to give apowdery solid composition.

COMPARATIVE EXAMPLE 10

In a mortar, 0.15 g of ubidecarenone, 0.3 g of sodium lauryl sulfate,2.49 g of D-mannitol and 0.06 g of hydroxypropyl cellulose (HPC-SSL)were mixed with a pestle to give a powdery solid composition.

COMPARATIVE EXAMPLE 11

In 30 ml of special grade ethanol, 0.03 g of Compound (Ib) wasdissolved, and then 0.9 ml of polysorbate 80 was added thereto anddissolved therein. After removing the ethanol by stirring under anitrogen gas stream, 30 ml of physiological saline (manufactured byOtsuka Pharmaceutical) was added to the residue to give an injectioncontaining 1 mg/ml of Compound (Ib).

TEST EXAMPLE 1

An amount corresponding to 10 mg of Compound (Ia) of each of the solidcompositions obtained in Examples 1 to 10 and Comparative Examples 1 to3 was poured into 20 ml of water at 37° C. Under paddle-stirring at 50rpm, the solution was sampled at 0.5 ml with the lapse of time andfiltered through a filter of 0.2 μm mesh. Then, the solubility ofCompound (Ia) was measured by high-performance liquid chromatography.

Table I shows changes in the solubility of Compound (Ia) with the lapseof time. TABLE 1 Changes in solubility of Compound (Ia) Dissolution testin 20 ml of water at 37° C. Solubility (μg/ml) 5 min 15 min 30 min 60min Example 1 35.64 35.44 35.36 38.98 Example 2 18.61 18.10 18.83 18.09Example 3 26.18 24.65 23.98 23.92 Comparative Example 1 4.26 3.78 3.884.06 Comparative Example 2 2.09 3.28 2.94 2.21 Comparative Example 31.86 1.91 0.50 0.16 Example 4 29.02 27.77 26.98 29.20 Example 5 26.6128.38 30.26 32.26 Example 6 11.54 23.13 23.96 23.70 Example 7 28.6028.49 25.58 25.90 Example 8 15.14 14.26 14.86 14.00 Example 9 23.1122.67 22.83 22.71 Example 10 117.14 118.06 116.09 —

As is apparent from Table 1, the solid compositions obtained in Examples1 to 10 showed higher solubility and solubility than the solidcompositions obtained in Comparative Examples 1 to 3, and kept the highsolubility even after 1 hour passed.

In the solid compositions of Examples 2 and 3 in which differenthydrophilic polymers were used, the high solubility was kept.

TEST EXAMPLE 2

Solubility of the capsule preparations obtained in Example 11 andComparative Examples 4 and 5 were tested in the same manner as in TestExample 1. Table 2 shows changes in solubility of Compound (Ia) with thelapse of time. TABLE 2 Changes in solubility of compound (Ia)Dissolution test in 20 ml of water at 37° C. Solubility (μg/ml) 5 min 15min 30 min 60 min Example 11 17.12 22.42 25.07 25.23 Comparative Example4 0.11 0.32 0.19 0.10 Comparative Example 5 1.10 2.12 1.60 0.90

TEST EXAMPLE 3

Oral absorbability (dog) of the capsule preparations obtained in Example11 and Comparative Examples 4 and 5 was evaluated. One capsule of eachpreparations was orally administered to a beagle and the blood of theanimal was collected at definite intervals. Next, the concentration ofCompound (Ia) in the plasma was measured by a high-performance liquidchromatography and the pharmacodynamic parameter was calculated.Regarding the capsules of Example 11 and Comparative Example 4, the meanand standard deviation of 3 cases were calculated, while concerning thecapsule preparation of Comparative Example 5, the mean and standarddeviation of 2 cases were calculated. FIG. 1 shows changes in theconcentration in plasma and Table 3 shows pharmacodynamic parameters. InTable 3, Tmax, Cmax and AUC_(0-∞) represent the time necessary forreaching the maximum concentration in blood (the time necessary forreaching the peak of the curve of concentration in blood), the maximumconcentration in blood (the concentration at the peak of the curve ofconcentration in blood), and the area under the curve of concentrationin blood from the initiation of the administration to the disappearanceof the medicament (the area under curve). TABLE 3 Pharmacodynamicparameter Tmax (h) Cmax (nmol/l) AUC_(0-∞) (nmol · h/l) Example 11 11.0± 11.8 42.4 ± 9.1  2865.7 ± 805.8  Comparative 10.0 ± 12.1 7.5 ± 5.8417.8 ± 310.1 Example 4 Comparative 13.0 14.3 1078.0 Example 5

As is apparent from Tables 2 and 3 and FIG. 1, the capsule preparationof Example 11 prepared by encapsulating the composition of the presentinvention showed higher solubility and higher oral absorbability thanthe capsule preparations of Comparative Examples 4 and 5 which wereprepared without wet granulation.

TEST EXAMPLE 4

Using 0.2 g (corresponding to 0.01 g of the medicament) of the solidcompositions obtained in Examples 12 and 13 and Comparative Examples 6and 7, the solubility of Compounds (Ib) and (Ic) were measured in thesame manner as in Test Example 1. Table 4 shows the results. TABLE 4Changes in solubility of compound (Ib) and compound (Ic) Dissolutiontest in 20 ml of water at 37° C. Solubility (μg/ml) 5 min 15 min 30 min60 min Example 12 67.5 54.4 48.7 52.1 Example 13 47.9 55.0 39.0 29.7Comparative Example 6 5.9 7.9 4.0 2.0 Comparative Example 7 1.7 1.8 1.91.9

As is apparent from Table 4, the solid compositions according to thepresent invention (Examples 12 and 13) showed higher solubility than thesolid compositions of Comparative Examples 6 and 7 which were preparedwithout wet granulation.

TEST EXAMPLE 5

A solid composition obtained in the same manner as in Example 4 wasstored at 40° C. under a relative humidity (RH) of 75% for 3 months.Using the solid composition before and after the storage, the solubilityof Compound (Ia) was examined in the same manner as in Test Example 1.Table 5 shows the results. TABLE 5 Dissolution test in 20 ml of water at37° C. Solubility (μg/ml) 5 min 15 min 30 min 60 min Before storage 27.027.4 20.4 29.5 After storage 22.8 23.3 23.4 24.0

As is apparent from Table 5, even after storage at 40° C. under arelative humidity (RH) of 75% for 3 months, the solid composition of thepresent invention (Example 4) showed high solubility in the same manneras in the level before the storage. Namely, it showed excellenttemperature- and humidity-stability.

TEST EXAMPLE 6

An amount corresponding to 10 mg of Compound (IIa) or (IIIa) of each ofthe powdery solid compositions obtained in Examples 14 and 15 andComparative Examples 8 and 9 was dropped into 20 ml of water at 37° C.Under paddle-stirring at 50 rpm, the solution was sampled at 0.5 ml withthe lapse of time and filtered through a filter having a pore size of0.8 μm. Then, the solubility of Compound (IIa) or (IIIa) was measured bya high-performance liquid chromatography.

Table 6 shows changes in solubility of each medicament with the lapse oftime. TABLE 6 Dissolution test in 20 ml of water at 37° C. Solubility(μg/ml) 5 min 15 min 30 min 60 min Example 14 7.2 7.2 6.6 6.6 Example 1520.1 19.2 19.7 19.1 Comparative Example 8 2.4 1.9 2.1 2.2 ComparativeExample 9 4.2 3.3 3.7 4.2

As is apparent from Table 6, the solid compositions of Examples 14 to 15showed higher solubility of Compounds (IIa) and (IIIa) than those ofComparative Examples 8 and 9 which were prepared without wetgranulation.

TEST EXAMPLE 7

An amount corresponding to 10 mg of ubidecarenone of each of the solidcompositions obtained in Examples 16 to 18 and Comparative Example 10was dropped into 20 ml of water at 37° C. Under paddle-stirring at 50rpm, the solution was sampled at 0.5 ml with the lapse of time andfiltered through a filter having a pore size of 0.8 μm. Then, thesolubility of ubidecarenone was measured by a high-performance liquidchromatography.

Table 7 shows changes in solubility of each medicament with the lapse oftime. TABLE 7 Dissolution test in 20 ml of water at 37° C. Solubility(μg/ml) 5 min 15 min 30 min 60 min Example 16 18.5 18.8 21.1 19.8Example 17 115.6 107.1 97.3 120.2 Example 18 34.9 29.5 27.2 29.6Comparative Example 10 0.2 0.3 0.3 0.3

As is apparent from Table 7, the solid compositions of Examples 16 to 18showed higher solubility of ubidecarenone than that of ComparativeExample 10 which was prepared without wet granulation.

TEST EXAMPLE 8

An amount corresponding to 10 mg of Compound (Ib) of each of the solidcompositions obtained in Examples 19 to 27 was dropped into 20 ml ofwater at 37° C. Under paddle-stirring at 50 rpm, the solution wassampled at 0.5 ml with the lapse of time and filtered through a filterhaving a pore size of 0.8 μm. Then, the solubility of Compound (Ib) wasmeasured by a high-performance liquid chromatography.

Table 8 shows changes in solubility of Compound (Ib) with the lapse oftime. TABLE 8 Dissolution test in 20 ml of water at 37° C. Solubility(μg/ml) 5 min 15 min 30 min 60 min Example 19 227.1 226.6 229.4 228.6Example 20 28.6 20.5 18.0 13.6 Example 21 62.4 64.7 59.2 42.2 Example 2285.1 82.9 82.6 82.6 Example 23 66.1 73.1 70.7 65.7 Example 24 84.1 84.182.6 80.6 Example 25 71.9 73.4 69.2 69.1 Example 26 72.4 72.6 67.0 67.2Example 27 74.7 74.4 68.5 64.5

As is apparent from Table 8, the solid compositions of Examples 19 to 27showed significantly higher solubility of Compound (Ib) than that ofComparative Example 6 which was prepared without wet granulation.

TEST EXAMPLE 9

Oral absorbability (dog) of the capsule preparations obtained inExamples 28 to 31 was evaluated. One capsule of each preparations wasorally administered to a beagle and the blood of the animal wascollected at definite intervals. Next, the concentration of Compound(Ib) in the plasma was measured by high-performance liquidchromatography. The pharmacodynamic parameter was calculated bydetermining the mean and standard deviation of 3 or 4 cases.Furthermore, 10 ml of the injection of Comparative Example 11 wasintravenously administered and blood collection, measurement andcalculation were carried out in the same manner.

FIG. 2 shows changes in the concentration in plasma and Table 9 showspharmacodynamic parameters. TABLE 9 Pharmacodynamic parameter AnimalCmax AUC_(0-∞) number Tmax (h) (nmol/l) (nmol · h/l) Example 28 4 1.5 ±0.6 84.0 ± 17.5 987 ± 351 Example 29 4 2.0 ± 1.4 18.0 ± 4.1  247 ± 129Example 30 3 1.5 ± 0.6 28.6 ± 12.8 323 ± 127 Example 31 4 2.7 ± 1.2 71.2± 29.7 722 ± 186 Comparative 3 0.083 ± 0.0  337.7 ± 46.0  1530 ± 310 Example 11

As is apparent from Table 9 and FIG. 2, the capsule preparationsprepared by encapsulating the compositions according to the presentinvention correlated to the solubility shown in Table 8 and showed highoral absorbability having 16 to 65% AUC of the case of the intravenousinjection (Comparative Example 11).

INDUSTRIAL APPLICABILITY

According to the present invention, a composition improved in thesolubility or oral absorbability of a slightly water-soluble componentcan be provided.

1. A composition which comprises three components of a slightlywater-soluble component, a surfactant and a hydrophilic polymer, and isobtainable by wet granulation in the presence of water.
 2. Thecomposition according to claim 1, wherein the slightly water-solublecomponent is a slightly water-soluble medicament.
 3. The compositionaccording to claim 1, wherein the slightly water-soluble component is aslightly water-soluble food component.
 4. The composition according toclaims 1, which comprises an excipient.
 5. The composition according toclaim 1, wherein the surfactant is one or more surfactants selected fromthe group consisting of sodium lauryl sulfate, polysorbate 80,polysorbate 60, polyoxyethylene hydrogenated castor oil, polyoxyethylenepolyoxypropylene glycol and sucrose fatty acid esters.
 6. Thecomposition according to claim 1, wherein the hydrophilic polymer is oneor more hydrophilic polymers selected from the group consisting ofhydroxypropyl cellulose, hydroxypropyl methyl cellulose, methylcellulose, carboxymethyl cellulose, carboxymethyl ethyl cellulose,hydroxypropyl starch, hydroxyethyl cellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methyl cellulose phthalate,carboxyvinyl polymer, polyvinylpyrrolidone, polyvinyl alcohol,methacrylic acid copolymers, macrogol, starch, gelatin, dextrin,pullulan, agar and acacia.
 7. The composition according to claim 1,wherein the hydrophilic polymer is one or more hydrophilic polymersselected from the group consisting of hydroxypropyl cellulose,hydroxypropyl methyl cellulose and polyvinylpyrrolidone.
 8. Thecomposition according to claim 4, wherein the excipient is one or moreexcipients selected from the group consisting of lactose, sucrose,starch, crystalline cellulose, D-mannitol, D-sorbitol, a starchderivative, a cellulose derivative, a carbonate, a phosphate and asulfate.
 9. The composition according to claim 4, wherein the excipientis one or more excipients selected from the group consisting of starch,crystalline cellulose and D-mannitol.
 10. The composition according toclaim 1, wherein the slightly water-soluble component is a steroidmedicament.
 11. (canceled)
 12. (canceled)
 13. (canceled)
 14. (canceled)15. The composition according to claim 1, wherein the surfactant issodium lauryl sulfate, and the hydrophilic polymer is hydroxypropylcellulose.
 16. The composition according to claim 1, wherein thesurfactant is sodium lauryl sulfate, and the hydrophilic polymer ishydroxypropyl methyl cellulose.
 17. The composition according to claim1, wherein the surfactant is sodium lauryl sulfate, and the hydrophilicpolymer is polyvinylpyrrolidone.
 18. The composition according to claim1, wherein the wet granulation is carried out by a wet granulationmethod by stirring.
 19. The composition according to claim 1, whereinthe slightly water-soluble component is ubidecarenone or a fat-solublevitamin.
 20. A method for improving the solubility of a slightlywater-soluble component, which comprises subjecting the slightlywater-soluble component to wet granulation together with a surfactantand a hydrophilic polymer in the presence of water.
 21. A method forimproving the oral absorbability of a slightly water-soluble component,which comprises subjecting the slightly water-soluble component to wetgranulation together with a surfactant and a hydrophilic polymer in thepresence of water.
 22. The composition according to claim 10, whereinthe surfactant is sodium lauryl sulfate, and the hydrophilic polymer ishydroxypropyl cellulose.
 23. The composition according to claim 10,wherein the surfactant is sodium lauryl sulfate, and the hydrophilicpolymer is hydroxypropyl methyl cellulose.
 24. The composition accordingto claim 10, wherein the surfactant is sodium lauryl sulfate, and thehydrophilic polymer is polyvinylpyrrolidone.